Fluoropheno-thiazine and pharmaceutical use

ABSTRACT

The compound 2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionic acid or a pharmaceutically acceptable salt thereof. The compound or salt are useful as antihistamines.

This application is a continuation, of application Ser. No. 759,504,filed 7/26/85, now abandoned which is a continuation of Serial No.678,338 filed Dec. 5, 1984, now abandoned and a continuation in part ofSerial No. 616,311 filed June 1, 1984, now abandoned.

The present invention relates to a new chemical compound exhibitingantihistamine and anti-allergic activity, to processes for preparing it,to novel intermediates involved in its preparation, to pharmaceuticalcompositions containing it and to its use in medicine.

U.S. Pat. No. 2,530,451 discloses a group of9-(dialkylaminoalkyl)phenothiazines with antihistamine activity, themost outstanding of which is the compound named, and hereinafterreferred to by its generic name, promethazine(10-(2-dimethylaminopropyl)phenothiazine). Promethazine has gained afair degree of clinical acceptance as a tranquillizer and as anantihistamine.

The antihistamines now in use, including diphenylhydramine, thepheniramines, pyrilamine, promethazine and triprolidine have onepotential disadvantage in common; they all cause sedation or drowzinessin some patients. Promethazine also has the additional disadvantage thatit has potent anticholinergic activity.

A novel compound having antiallergic activity in vivo as defined byblockade of anaphylactoid activity has now been discovered, and strongantihistamine activity and appear to be substantially free of CNSside-effects and to possess markedly less anticholinergic activity thanpromethazine.

Accordingly this invention provides a compound of the formula (I) whichhas the chemical name2-[10-(2-dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid, or a salt, ester or amide thereof. ##STR1##

Solvates of the compound of the formula (I) are also included within thescope of the present invention. Preferred solvates include hydrates andC₁₋₄ alkanolates.

Esters and amides of the compound of the formula (I) whilst havingantihistamine activity in their own right may also be usefulintermediates in the preparation of the carboxy compound of the formula(I). Suitable esters include conventional ester groups known to beuseful for protecting carboxylic acid group such as C₁₋₆ alkyl esterswherein the alkyl group is straight or branched chain and is optionallysubstituted by halogen. Alkyl esters (C₁₋₄) are particularly preferred.Salts of the compound of formula (I) may be either acid addition saltsor salts formed with the carboxylic acid group. Acid addition salts arepreferred but salts formed from the carboxylic acid group may beparticularly useful in preparing the corresponding carboxy compound.Pharmaceutically acceptable salts are preferred.

When used in medicine, the salts of the compound of formula (I) shouldbe both pharmacologically and pharmaceutically acceptable, but nonpharmaceutically acceptable salts may conveniently be used to preparethe free active compound or pharmaceutically acceptable salts thereofand are not excluded from the scope of this invention. Suchpharmacologically and pharmaceutically acceptable acid addition saltsinclude, but are not limited to, those prepared from the followingacids: hydrochloric, sulfuric, nitric, phosphoric, maleic, salicyclic,p-toluenesulphonic, tartaric, citric, methanesulphonic, formic, malonic,isothionic, succinic, naphthalene-2-sulphonic and benzenesulphonic.Also, pharmaceutically acceptable salts can be prepared as alkalinemetal or alkaline earth salts, such as sodium, potassium or calciumsalts of the carboxylic acid group.

The present invention also provides analogy methods for preparingcompounds of formula (I), for example:

(a) A compound of the formula (I) may be prepared by the reaction of acompound of formula (II): ##STR2## wherein L is a leaving group; or anester thereof with an amine HN(CH₃)₂.

(b) The compound of formula (I) may also be prepared by the oxidation ofthe corresponding aldehyde (III): ##STR3##

(c) An alternate synthetic route to the compound of formula (I) is thehydrolysis of a compound of formula (IV): ##STR4## wherein Z is CN,CONR¹ R¹ or CO₂ R¹ or CO₂ R¹ (R¹ is C₁₋₄ alkyl); or--CH═C(Y) XH X isoxygen or sulphur and Y is a secondary amino group;

(d) The alkylation of a compound for formula (V) may also be used toprepare the company of formula (I): ##STR5## wherein COR₂ is an ester oramide group and thereafter, optionally converting the compound offormula (I) to the acid an amide or another salt by methods well knownto those skilled in the art.

Suitable leaving group L in the compounds of the formula (III) are thoseas defined by J. March, Advanced Organic Chemistry, 2nd ed., pages 683and 895, McGraw Hill, New York, 1977, e.g.--Br,--Cl, toluene-sulphonate,methanesulphonate, acyloxy (such as acetate), etc.

This reaction will normally be carried out in a solvent suitable forcarrying out such displacement reactions, for example a polar solvent,such as a C₁₋₄ alkanol or a polar aprotic solvent such as DMSO, at atemperature between 0° and 180° C.

The compounds of the formula (II) may be prepared by the reaction of anester of the corresponding compound where L is a hydroxy group with anacid or a suitable reactive acid derivative, followed by removal of theester function if desired. Suitable reactants include hydrogen halideshalogenated phosphorus compounds such as phosphorus pentachloride orphosphorus oxychloride, a suitable sulphonyl chloride (such asmethanesulphonyl chloride or p-toluenesulphonyl chloride) or an acidanhydride such as acetic anhydride. The reaction will conveniently becarried out in a suitable solvent under conditions well known to thoseskilled in the art, for example a non-protic solvent such as an ether ora halogenated hydrocarbon, in the presence of a base such as a tertiaryamine (for example triethylamine) at a non-extreme temperature, forexample between 0° and 100° C. and conveniently at room temperature.When a tertiary amine is used as a base, an excess of this may be usedas the solvent. Those intermediates that are novel form an importantfurther aspect of the present invention.

The compound of this invention has antiallergic activity and may be usedfor the same indications as clinically used antiasthmatic compounds,namely to help to control bronchoconstriction or brochospasmcharacteristic of allergic asthma and exercise induced asthma and thesymptoms of bronchoconstriction and bronchospasm resulting from acute orchronic bronchitis. The compound is believed to inhibit the release ofautacoids (i.e. histamine, serotonin and the like) from mast cells andto inhibit directly the antigen-induced production of histamine. Thus,it may be classified as a mast cell stabilizer with antihistaminicaction.

The compound of this invention also has strong antihistamine activityand may be used for the same indications as clinically usedantihistamines, namely to relieve detrimental symptoms (caused byhistamine release) of nasal stuffiness due to colds and vasomotorrhinitis and for the symptomatic control of allergic conditionsincluding nasal allergy, perennial rhinitis, urticaria, angioneuroticoedema, allergic conjunctivitis, food allergy, drug and serum reactions,insect bites and strings and desensitizingreactions. The compound mayalso be used in conditions responsive to its antipruritic activityincluding allergic dermatoses, neurodermatitis, anogenital pruritus, andpruritus of nonspecific origin such as eczema, and of specific causesuch as chickenpox, photosensitivity and sunburn. The present inventiontherefore provides a method for the symptomatic treatment of allergicconditions by the administration of an effective amount of the compoundof formula (I).

The present invention also provides a method for the antagonism ofendogenously released histamine by the administration of an effectiveamount of the compound of formula (I).

The amount of the compound of formula (I), also referred to as the"active compound", required for use in the above conditions will varywith the compound chosen, the route of administration and the conditionand mammal undergoing treatment, and is ultimately at the discretion ofthe physician. A suitable oral dose of the active compound for a mammalis in the range of from 0.003 to 1.0 mg per kilogram body weight perday; preferably from 0.04 to 0.24 mg/kg. For example a typical dose fora human recipient of compound (B) (see Example 2 and Table 1 hereafter)is between 0.03 and 0.1 mg/kg body weight per day.

The desired daily dose is preferably presented as from one to sixsubdoses administered at appropriate intervals throughout the day asneeded. Where three subdoses of the compound of formula (I) areemployed, each will preferably lie in the range of from 0.014 to 0.08mg/kg body weight; for example, a typical sub-dose of such a compoundfor a human recipient is between 1 and 20 mg, for example 4 or 8 mg.

Whilst it is possible for a compound of formula (I) to be administeredalone as the raw chemical, it is preferable to present the compound offormula (I) as a pharmaceutical formulation. Thus, the present inventionalso provides pharmaceutical formulations, both for veterinary and forhuman medical use, which comprise the compound of formula (I) togetherwith one or more pharmaceutically acceptable carriers therefor andoptionally any other therapeutic ingredients. For example, the activecompound may be formulated with a sympathomimetic agent such as thedecongestant pseudoephedrine, an antitussive such as codeine, ananalgesic, an antiinflammatory, an antiphretic, or an expectorant. Thecarrier(s) must be pharmaceutically acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The formulations include those suitable for oral, rectal, topical,nasal, ophthalmic or parenteral (including subcutaneous, intramuscularand intravenous) administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound(defined herein as a compound of formula (I)); as a powder or granules;or a suspension in an aqueous liquid or nonaqueous liquid such as asyrup, and elixir, an emulsion or a draught. A tablet may be made bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine, with the active compound being in a free-flowing formsuch as a powder or granules which is optionally mixed with a binder,disintegrant, lubricant, inert diluent, surface active agent ordispersing agent. Molded tablets comprised of a mixture of the powderedactive compound with any suitable carrier may be made by molding in asuitable machine.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar for example sucrose to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavourings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredient, such as apolyhydric alcohol, for example glycerol or sorbitol, and suitablepreservatives.

Formulations for rectal administration may be presented as a suppositorywith a usual carrier such as cocoa butter, or hydrogenated fats orhydrogenated fatty carboxylic acids.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient.

Nasal spray formulations comprise purified aqueous solutions of theactive compound with preservative agents and isotonic agents. Suchformulations are adjusted to a pH and isotonic state compatible with thenasal mucous membranes.

Ophthalmic formulations are prepared by a similar method to that for thenasal spray except that the pH and isotonic factors are adjusted tomatch those of the eye.

Topical formulations comprise the active compound dissolved or suspendedin one or more media such as mineral oil, petroleum, polyhydroxylalcohols or other bases used for topical pharmaceutical formulations.The addition of other accessory ingredients, vide infra, may bedesirable.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavouring agents, binders,disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants) and the like. The presentinvention also provides the first use of the compounds of formula (I) inmedicine.

The following Examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof. All temperatures indicated are in degrees Celsius.

EXAMPLE 12-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid

(a) Ethyl 2-methyl-2-3-nitro-4-(4-fluorophenylthio)phenyl]propionate(Compound ex-17a)

A mixture of Ethyl 2-(4-bromo-3-nitrophenyl)-2-methylpropionate (54.5g), 4-fluorothiophenol (27 g) and Na₂ CO₃ (39.2 g) in ethanol (250 mL)was stirred under nitrogen at reflux for 5 hours. It was poured intoice-cold water (1500 mL), stirred well, and the resulting yellow solidwas filtered. This solid was dissolved in ether (400 mL), washed with2%NaOH, and then dried (MgSO₄) and evaporated. The product, compoundex-17a, was obtained in quantitative yield as a yellow solid. Its tlcwas essentially homogeneous and its nmr spectrum was consistent with thestructure indicated. Compound ex-17a was recrystallized from2-propanol/hexane to give a yellow solid, mp 56°-60° C.

(b) Ethyl 2-methyl-2-(7-fluoro-2-phenothiazinyl)propionate. (Compoundex-17b)

Compound ex-17a (24.3 g) and triethyl phosphite (46.0 g, were combinedin dried and deoxygenated n-propylbenzene (200 mL) and refluxed under N₂for 4 hours. The volatile components were removed on the water aspiratorat 80° C. The crude product was purified to apparent homogeneity byflash chromatography on silica gel, eluting contaminants withhexane/ethyl acetate (20:1) and then eluting the product withhexane/ethyl acetate (10:1). The product, compound ex-17b, wascrystallized from CH₂ Cl₂ /hexane, mp 116°-118° C.

(c) Ethyl2-[10-(2-dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionate.(Compound ex-17c)

Compound ex-17b (4.0 g) and potassium t-butoxide (1.52 g) were combinedin dry deoxygenated toluene (30 mL) and stirred under N₂ for 10 minutes.2-chloro-1-dimethylaminopropane (1.7 g) was added, and the reaction washeated at 80° C. for 1 hour. A further 1.5 g potassium t-butoxide and1.7 g 2-chloro-1-dimethylaminopropane were added and stirring andheating were continued for 2 hours. The reaction was diluted withtoluene (50 mL) and washed with water and saturated NaCl. The amineswere then extracted into dilute HCl, which was washed once with toluene,basified (litmus, conc NH₄ OH), and extracted with CHCl₃. Evaporation ofthe CHCl₃ yielded the crude product. This product was purified bypreparative HPLC using silica gel columns in series. The elutionsolvents, in sequence, were: hexane/ethyl acetate/ethanol (38:38:3, then20:20:2.7, then 18:18:3), then changing components to ethylacetate/ethanol (10:1 and finally 5:1). The free base was a viscous oilfrom which a crystalline salt was made using HCl/ether andrecrystallizing from 2-propanol/ether, giving compound ex-17chydrochloride, mp 156°-160° C. Elemental, nmr and mass spectral analyseswere consistent with the structure indicated.

(d)2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazine]-2-methylpropionicacid.

Compound ex-17c hydrochloride (0.5 g) was suspended in a mixture of 1.0Nsodium hydroxide (5.0 mL) and ethanol (5.0 mL). The suspension washeated at reflux for 48 hr and then evaporated to dryness. The residuewas dissolved in water (12 mL). The solution was filtered, washed withether and then acidified with 1.0N hydrochloric acid (7.0 mL). Thesolution was evaporated to dryness. The residue was digested with2-propanol (24 mL) and the mixture filtered and evaporated. The residuewas recrystallized from methanol/ethyl acetate to give compound2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid hydrochloride, mp 180°-186° C. Elemental analysis, Nmr and massspectral analyses were consistent with the structure assigned.

2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid may be isolated as the free amino acid by carefully neutralizing anaqueous solution of the hydrochloride, thereby precipitating the freeamino acid compound2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid.

The sodium salt of2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid may be prepared by adding this compound to a slight molar excess ofaqueous sodium hydroxide and then salting out the sodium salt of2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid by adding sodium chloride to the solution. Alternatively,2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid may be added to an aqueous solution of sodium hydroxide containingan equimolar amount of sodium hydroxide and then lyophylizing thesolution to give the sodium salt.

EXAMPLE 2 Antihistamine Activity

A. In vitro antihistamine activity: The longitudinal muscle was isolatedfrom the intact ileum of guinea-pigs (Hartley, male 250-400 g) andplaced in an organ bath under 300 mg tension. After one hour ofequilibration, cumulative concentration-response curves (Van Rossum, J.M., Arch. Int. Pharmacodyn. Ther. 143, 299-330, 1963) to histamine wereobtained. Following washing, the tissues were incubated for one hourwith the test compound and then a second histamine concentrationresponsecurve was run. Shifts to the right of the agonist concentration-responsecurve produced by the antagonists were used to construct Schild plots(Arunlakshana, O. and Schild, H. O., Br. J. Pharmacol. 14, 48-58, 1959).Regression of Log (dr-1) on Log [B], where dr is an equiactive responsein the presence and absence of antagonist and [B] is the molarconcentration of antagonist, allowed an estimate of pA₂, i.e. thenegative log of the concentration of antagonist which shifts the controlhistamine concentration response curve 2X to the right. The pA₂ valuefound for the compound of formula (I) is 8.6.

B. In vivo Antihistaminic Activity: Guinea pigs (Hartley, male, 300-350g) were fasted for 20 hours and then dosed p.o. or i.p. with the testcompound. One hour after dosing, on an individual basis, the guinea pigswere placed in a clear plastic chamber which was saturated andcontinually gassed with 0.25% histamine from an aerosol nebulizer. Theguinea pigs were monitored for signs of histamine anaphylaxis (e.g.cough, sneeze, strong abdominal movements, cyanoses or loss ofrighting). Under the test conditions, control animals collapsed onaverage within 33 seconds. ED₅₀ 's for protection against histamine werecalculated by probit analysis.

In this test the ED₅₀ indicates that at that particular dose 50% of theanimals were completely protected against histamine challenge at thetime of testing (1 hour post-dosing). Complete protection was defined asno histamine symptoms for six minutes in the aerosol chamber(approximately 10X the collapse time of the control animals). The ED₅₀for the compound of formula (I) was found to be 0.04≦1 mg/kg p.o. and aduration of action from 4 to 30 hrs.

EXAMPLE 3 Formulations

    ______________________________________                                        (A)-Injection                                                                 Ingredient        Amount per ampoule                                          ______________________________________                                        Compound of formula (I)                                                                         1.0        mg                                               Water for injections, q.s.                                                                      1.0        mL                                               ______________________________________                                    

The finely ground active compound was dissolved in the water forinjections. The solution was filtered and sterilized autoclaving.

    ______________________________________                                        (B)-Suppository                                                               Ingredient       Amount per suppository                                       ______________________________________                                        Compound of Formula (I)                                                                        1.0          mg                                              Cocoa Butter     q.s. to 2.0  g                                               or Wecobee ™ Base                                                          ______________________________________                                         Wecobee is a trademark and is a hydrogenated fatty carboxylic acid.      

The finely ground active compound was mixed with the melted suppositorybase (either Cocoa Butter or Wecobee™ base), poured into moulds andallowed to cool to afford the desired suppositories.

    ______________________________________                                        (C)-Syrup                                                                     Ingredient         Amount per mL                                              ______________________________________                                        Compound of Formula (I)                                                                          1.0         mg                                             Ethanol            0.3         mg                                             Sucrose            2.0         mg                                             Methylparaben      0.5         mg                                             Sodium Benzoate    0.5         mg                                             Cherry Flavour     q.s.                                                       Colouring          q.s.                                                       Water              q.s. to 5.0 mL                                             ______________________________________                                    

Ethanol, sucrose, sodium benzoate, methylparaben, and flavouring werecombined in 70% of the total batch quantity of water. Colouring and theactive compound were dissolved in the remaining water, then the twosolutions were mixed and clarified by filtration.

    ______________________________________                                        (D)-Tablet                                                                    Ingredient         Amount per Tablet                                          ______________________________________                                        Compound of Formula (I)                                                                          1.0        mg                                              Lactose            110.0      mg                                              Corn Starch, Pregelatinized                                                                      2.5        mg                                              Potato Starch      12.0       mg                                              Magnesium stearate 0.5        mg                                              ______________________________________                                    

The active compound was finely ground and intimately mixed with thepowdered excipients lactose, corn starch, potato starch and magnesiumstearate. The formulation was then compressed to afford a tabletweighing 126 mg.

    ______________________________________                                        (E)-Capsule                                                                   Ingredient        Amount per Capsule                                          ______________________________________                                        Compound of Formula (I)                                                                         1.0         mg                                              Lactose           440.0       mg                                              Magnesium Stearate                                                                              5.0         mg                                              ______________________________________                                    

The finely ground active compound was mixed with the powdered excipientslactose, and magnesium stearate and packed into gelatin capsules.

    ______________________________________                                        (F)-Tablet                                                                    Ingredient       Amount per Tablet                                            ______________________________________                                        Compound of Formula (I)                                                                        1.0         mg                                               Pseudoephedrine HCl                                                                            60.0        mg                                               Lactose          62.5        mg                                               Potato Starch    14.0        mg                                               Magnesium Stearate                                                                             1.0         mg                                               Gelatin          2.8         mg                                               ______________________________________                                    

A tablet was prepared from the above formulation by the methodpreviously described in Example 3(D).

    ______________________________________                                        (G)-Syrup                                                                     Ingredient        Amount per 5 mL                                             ______________________________________                                        Compound of Formula (I)                                                                         1.0         mg                                              Pseudoephedrine HCl                                                                             30.0        mg                                              Codeine Phosphate 10.0        mg                                              Guaifenesin       100         mg                                              Methylparaben     0.5         mg                                              Sodium benzoate   0.5         mg                                              Flavour           q.s.                                                        Glycerol          500         mg                                              Sucrose           2000        mg                                              Purified Water q.s. to                                                                          5.0         mL                                              ______________________________________                                    

A syrup containing other active ingredients in addition to a compound offormula (I) was prepared from the above ingredients by an analogousmethod to that described for Example 3(C) above.

    ______________________________________                                        (H)-Nasal Spray                                                               Ingredient        Amount per 100.0 mL                                         ______________________________________                                        Compound of Formula (I)                                                                         1           g                                               Sodium Chloride   0.8         g                                               Preservative      0.5         g                                               Purified Water q.s.                                                                             100.0       mL                                              ______________________________________                                    

The preservative was dissolved in warm purified water and after coolingto 25°-30° C. the sodium chloride and the compound of formula (I) wereadded. The pH was then adjusted to 5.5-6.5 and purified water was addedto bring the final volume to 100.0 mL.

    ______________________________________                                        (I)-Ophthalmic Solution                                                       Ingredient        Amount per 100.0 mL                                         ______________________________________                                        Compound of Formula (I)                                                                         0.1         g                                               Sodium Chloride   0.8         g                                               Preservative      0.5         g                                               Water for Injection q.s.                                                                        100.0       mL                                              ______________________________________                                    

This formulation was prepared in a similar way to the nasal spray.

    ______________________________________                                        (J)-Topical Cream                                                             Ingredient       Amount per 100.0 g                                           ______________________________________                                        Compound of Formula (I)                                                                        0.1         g                                                Emulsifying Wax, N.F.                                                                          15.0        g                                                Mineral Oil      5.0         g                                                White Petrolatum 5.0         g                                                Preservative     0.25        g                                                Purified Water q.s.                                                                            100.0       g                                                ______________________________________                                    

The preservative was dissolved in approximately 50 g of warm purifiedwater and after cooling to about 25°-30° C. the compound of formula (I)was added. In a separate container the emulsifying wax, mineral oil andwhite petrolatum were mixed well and heated to approximately 70°-80° C.The aqueous solution containing the compound of formula (I) was added tothe warm mixture of emulsifyng wax, mineral oil and petrolatum withvigorous mixing while cooling to 25° C. Additional purified water wasadded with mixing to bring the total weight of the cream to 100.0 g.

I claim:
 1. A compound which is2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid or a salt, ester or amide thereof. 2.2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid or a pharmaceutically acceptable salt thereof.
 3. The compound ofclaim 1 as the hydrochloride salt.
 4. The compound of claim 1 as asodium salt.
 5. The compound of claim 1 as the ethyl ester.
 6. Apharmaceutical composition comprising2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid or a pharmaceutically acceptable salt thereof together with acarrier therefor.
 7. A method of relieving the detrimental effects ofhistamine in a mammal comprising administering to said mammal aneffective amount of2-[10-(2-Dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid or a salt, ester or amide thereof.
 8. A method of claim 7 whereinthe compound is administered as hydrochloride salt.
 9. A method of claim7 wherein the compound is administered as the sodium salt.
 10. A methdof claim 7 wherein the compound is administered as the ethyl ester. 11.A method of claim 7 wherein the mammal is a human.
 12. A method of claim7 wherein the detrimental symptom is selected from the group comprisingnasal allergy, perennial rhinitis, urticaria, antioneurotic oedema,allergic conjectivitis, food allergy, drug and serum reactions, insectbites and stings, desensitising reactions.
 13. The method of claim 7 inwhich2-[10-(2-dimethylaminopropyl)-7-fluoro-2-phenothiazinyl]-2-methylpropionicacid is administered.
 14. The method of claim 7 in which apharmaceutically acceptable salt of2-[10(2-dimethylaminopropyl)-7-fluro-2-phenothiazinyl-2-methylpropionicacid is administered.